Filosa Rosanna, Peduto Antonella, Micco Simone Di, Caprariis Paolo de, Festa Michela, Petrella Antonello, Capranico Giovanni, Bifulco Giuseppe
Department of Pharmaceutical Science, University of Salerno, via Ponte Don Melillo, variante 11C, 84084 Fisciano, Italy.
Bioorg Med Chem. 2009 Jan 1;17(1):13-24. doi: 10.1016/j.bmc.2008.11.024. Epub 2008 Nov 18.
A series of bisnaphthalimide derivatives were synthesized and evaluated for growth-inhibitory property against HT-29 human colon carcinoma. The N,N'-bis[2-(5-nitro-1,3-dioxo-2,3-dihydro-1H-benz[de]-isoquinolin-2-yl)]propane-2-ethanediamine (9) and the N,N'-Bis[2-(5-nitro-1,3-dioxo-2,3-dihydro-1H-benz[de]-isoquinolin-2-yl)]butylaminoethyl]-2-propanediamine (12) derivatives emerged as the most potent compounds of this series. Molecular modelling studies indicated that the high potency of 12, the most cytotoxic compound of the whole series, could be due to larger number of intermolecular interactions and to the best position of the naphthalimido rings, which favours pi-pi stacking interactions with purine and pyrimidine bases in the DNA active site. Moreover, 12 was designed as a DNA topoisomerase II poison and biochemical studies showed its effect on human DNA topoisomerase II. We then selected the compounds with a significant cytotoxicity for apoptosis assay. Derivative 9 was able to induce significantly apoptosis (40%) at 0.1 microM concentration, and we demonstrated that the effect on apoptosis in HT-29 cells is mediated by caspases activation.
合成了一系列双萘二甲酰亚胺衍生物，并评估了它们对HT - 29人结肠癌细胞的生长抑制特性。N,N'-双[2-(5-硝基-1,3-二氧代-2,3-二氢-1H-苯并[de]异喹啉-2-基)]丙烷-2-乙二胺（9）和N,N'-双[2-(5-硝基-1,3-二氧代-2,3-二氢-1H-苯并[de]异喹啉-2-基)]丁基氨基乙基]-2-丙二胺（12）衍生物是该系列中最有效的化合物。分子模拟研究表明，整个系列中细胞毒性最强的化合物12具有高效性，可能是由于其分子间相互作用数量较多，以及萘二甲酰亚胺环的位置最佳，有利于与DNA活性位点中的嘌呤和嘧啶碱基形成π-π堆积相互作用。此外，12被设计为一种DNA拓扑异构酶II毒药，生化研究表明了它对人DNA拓扑异构酶II的作用。然后我们选择了具有显著细胞毒性的化合物进行凋亡检测。衍生物9在0.1微摩尔浓度下能够显著诱导凋亡（40%），并且我们证明了其对HT - 29细胞凋亡的影响是由半胱天冬酶激活介导的。
